This proposal will investigate excitation-contraction (EC) coupling in the hypertrophied and failing hearts of SHHF/Mcc-facp (SHF) rats. The SHF rat is spontaneously hypertensive and typically dies of heart failure between one and two years of age. Specific aim #1 will test the hypothesis that the major components linking excitation to Ca2+ release from the sarcoplasmic reticulum (SR) are present in normal amounts in the failing SHF rat heart. Specific aim #2 will examine b-adrenergic modulation of EC coupling. Specific aim #3 will test the hypothesis that the functional coupling between the L-type Ca2+ release channels of the sarcolemma and the Ca2+ release channels, or ryanodine receptors, of the SR declines during the cellular remodeling that occurs as SHF hearts hypertrophy and eventually fail. Myocardial function will be characterized in vivo using echocardiography and in vitro with Langendorff perfused ventricles and single isolated left ventricular myocytes. In vitro studies will examine the effects of varied stimulation patterns and the effects of b1- and b2-adrenergic agonists. The relationship between L-type Ca2+ current and SR Ca2+ release events (Ca2+ sparks) will be examined using line scanning laser confocal microscopy of cells loaded with the fluorescent dye, fluo-3. The in vivo and in vitro functional data will be correlated with protein content and phosphorylation status of phospholamban and the ryanodine receptors in hearts from lean male SHF rats with heart failure, and from age-matched SHF rats with compensatory hypertrophy and normal Sprague-Dawley rats.